This research will focus on designing new interfacial coatings for gold nanorods with unprecedented sensitivity, imaging depth, and resolution for photoacoustic imaging (PAI). In typical contrast-enhanced PAI, pulsed laser light is absorbed by a NIR-absorbing nanostructure, leading to local heating, thermal expansion, and the generation of acoustic waves that are detected on the surface of the patient. As compared to all-optical imaging approaches such as fluorescence microscopy or optical coherence tomography, PAI allows for high resolution imaging of optical contrast deep below the tissue surface. Nevertheless, PAI of targeted contrast agents is ultimately limited by the amount of light that reaches the agents, photoacoustic conversion efficiency, and the need to distinguish the agents from background absorbers. The photoacoustic response of contrast agents is often linear with laser fluence, making it difficult to isolate the agents from the background. The proposed contrast agents will utilize novel porous coatings that entrap air, thereby greatly increasing the acoustic response of encapsulated gold nanorods (AuNRs). Hydrophobically-modified porous silica coatings will add two benefits beyond standard photoacoustic contrast agents. First, air has a thermal expansion coefficient two orders of magnitude higher than gold or silica, which should produce a larger acoustic signal at low laser fluences. More importantly, the formation of hydrophobic surfaces with amphiphilic coatings will stabilize the formation of nuclei for cavitation. Because cavitation has a much stronger acoustic response than thermal expansion, it is anticipated that the total acoustic response will be nonlinear with laser fluence. By specifically tuning the surface chemistry of the nanostructures, the amount of energy required to generate cavitation is reduced to the point that nonlinear signal generation can be induced at clinically-relevant laser intensities. This highly multidisciplinary research will be carried out through the PIs? complementary areas of expertise. PI Cha?s group will synthesize the AuNRs coated with nano- and mesoporous silica coatings with the intended NIR absorption profile. PI Goodwin?s group will tune the properties of the silica coatings to provide optimal nucleation of gas bubbles on the contrast agent surface and also design in vitro models for imaging. Finally, PI Murray?s lab will test the photoacoustic response at NIR wavelengths and conduct imaging studies. The ultimate goal will be to build from these initial proof-of-principle studies towards future work in clinical validation and translation via the following aims: (1) Build AuNR-hMSN Nanostructures and Optimize Their Surface Chemistry for Facilitating Cavitation; (2) Characterize Optical Properties and Nonlinear Photoacoustic Response of AuNR- hMSN Nanostructures; (3) Validate PAI Contrast of AuNR-hMSNs in a Scattering In Vitro Spheroid Model.